rs4887379

Variant names:

• chr15-88184105-C-G
• rs4887379
• NM_001012338.3:c.323+120G>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001012338.3(NTRK3):​c.323+120G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.212 in 959,686 control chromosomes in the GnomAD database, including 22,800 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.24 (4532 hom., cov: 32)
  • Exomes 𝑓: 0.21 (18268 hom.)
• Consequence: NTRK3 NM_001012338.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.165
• Publications: 4 publications found

Genes affected

NTRK3 (HGNC:8033): (neurotrophic receptor tyrosine kinase 3) This gene encodes a member of the neurotrophic tyrosine receptor kinase (NTRK) family. This kinase is a membrane-bound receptor that, upon neurotrophin binding, phosphorylates itself and members of the MAPK pathway. Signalling through this kinase leads to cell differentiation and may play a role in the development of proprioceptive neurons that sense body position. Mutations in this gene have been associated with medulloblastomas, secretory breast carcinomas and other cancers. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2011]

NTRK3 Gene-Disease associations (from GenCC):

• congenital heart disease

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 15-88184105-C-G is Benign according to our data. Variant chr15-88184105-C-G is described in ClinVar as Benign. ClinVar VariationId is 1282760.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.303 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001012338.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NTRK3	NM_001012338.3	MANE Select	c.323+120G>C		intron	N/A	NP_001012338.1
	NTRK3	NM_001375810.1		c.323+120G>C		intron	N/A	NP_001362739.1
	NTRK3	NM_001375811.1		c.323+120G>C		intron	N/A	NP_001362740.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NTRK3	ENST00000629765.3	TSL:1 MANE Select	c.323+120G>C		intron	N/A	ENSP00000485864.1
	NTRK3	ENST00000557856.5	TSL:1	c.323+120G>C		intron	N/A	ENSP00000453959.1
	NTRK3	ENST00000558676.5	TSL:1	c.323+120G>C		intron	N/A	ENSP00000453511.1

Frequencies

GnomAD3 genomes AF: 0.236 AC: 35891 AN: 151978 Hom.: 4528 Cov.: 32

Gnomad AFR AF: 0.308

Gnomad AMI AF: 0.215

Gnomad AMR AF: 0.261

Gnomad ASJ AF: 0.198

Gnomad EAS AF: 0.150

Gnomad SAS AF: 0.296

Gnomad FIN AF: 0.136

Gnomad MID AF: 0.326

Gnomad NFE AF: 0.207

Gnomad OTH AF: 0.235

GnomAD4 exome AF: 0.207 AC: 167279 AN: 807592 Hom.: 18268 AF XY: 0.210 AC XY: 88472 AN XY: 421046

African (AFR) AF: 0.306 AC: 6139 AN: 20074

American (AMR) AF: 0.254 AC: 8890 AN: 34986

Ashkenazi Jewish (ASJ) AF: 0.194 AC: 4143 AN: 21312

East Asian (EAS) AF: 0.158 AC: 5247 AN: 33170

South Asian (SAS) AF: 0.282 AC: 18803 AN: 66744

European-Finnish (FIN) AF: 0.140 AC: 6681 AN: 47848

Middle Eastern (MID) AF: 0.237 AC: 741 AN: 3132

European-Non Finnish (NFE) AF: 0.200 AC: 108237 AN: 541438

Other (OTH) AF: 0.216 AC: 8398 AN: 38888

GnomAD4 genome AF: 0.236 AC: 35919 AN: 152094 Hom.: 4532 Cov.: 32 AF XY: 0.234 AC XY: 17382 AN XY: 74356

African (AFR) AF: 0.308 AC: 12764 AN: 41454

American (AMR) AF: 0.261 AC: 3993 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.198 AC: 688 AN: 3472

East Asian (EAS) AF: 0.150 AC: 777 AN: 5174

South Asian (SAS) AF: 0.295 AC: 1424 AN: 4820

European-Finnish (FIN) AF: 0.136 AC: 1442 AN: 10592

Middle Eastern (MID) AF: 0.330 AC: 97 AN: 294

European-Non Finnish (NFE) AF: 0.207 AC: 14039 AN: 67968

Other (OTH) AF: 0.237 AC: 499 AN: 2108

Alfa AF: 0.210 Hom.: 410

Bravo AF: 0.245

Asia WGS AF: 0.253 AC: 881 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.1
DANN	Benign	0.33
PhyloP100		-0.17
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs4887379; hg19: chr15-88727336;